17 Embryonic development (CNS)

Question 1

What is the embryological origin of neural and glial cells?

Answer 1

Neuroectoderm

Question 2

What is the origin of basal (motor) plate?

Answer 2

The ventral (‘lower’) side of the neural tube
So ectoderm

Question 3

What is the origin of the alar (sensory) plate?

Answer 3

The dorsal (‘upper’) side of the neural tube
Ectoderm

Question 4

What are neural crest cells?

Answer 4

• Cells released from the dorsal lip when the neural tube is closing
  
  • Neural tube cells undergo epithelial-to-mesenchymal transition (EMT), delaminate and migrate to the periphery
• These cells are essentially a sea of stem cells that can then migrate and differentiate to form a wide range of cells in the periphery
  
  • The PNS is derived from neural crest cells

Question 5

What are the derivatives of NCCs?

Answer 5

Neural aspects e.g. ganglia

Melanocytes

Enteric nervous system

Question 6

Can mature neurons undergo mitosis?

Answer 6

No

Question 7

Where are the sites of adult neurogenesis?

Answer 7

Sub-ventricular zone and dentate gyrus.

Question 8

What are the first three regions of the developing brain that form?

Answer 8

Forebrain = prosencephalon
Midbrain = mesencephalon
Hindbrain = rhombencephalon

Question 9

What are the 5 secondary vesicles the 3 primary vesicles? What adult structures do these eventually develop into?

Answer 9

Question 10

What are the different steps of CNS development? (Brief)

Answer 10

• Neural induction
• Neurogenesis
• Cell differentiation
• Differentiation of connections
• Specialisation within the CNS
• Early spontaneous activity within the CNS
• Sensory connectivity patterns
• Plasticity

Question 11

What is neural induction? (Brief)

Answer 11

• This is where the CNS is developed from the neural plate
• The plate closes to form the neural tube
  
  • This tube is patterned in a longitudinal and ventral/dorsal pattern
  • Longitudinal patterning by Hox genes
  • Ventral/dorsal patterning by interactions from the surrounding mesoderm
• The rostral end of the neural tube forms the telencephalic vesicles, including the cerebral cortex (largest part of the brain)
• This process is linked to and occurs shortly after gastrulation

Question 12

What occurs prior to neural induction?

Answer 12

• Fertilised egg divides and then invades the endometrium of the uterus
• The placenta, bilaminar and eventually trilaminar disc is formed
  
  • Trilaminar disc is formed during gastrulation

Question 13

What is gastrulation?

Answer 13

• This is the conversion of the bilaminar disc (made up of hypoblast and epiblast) into the trilaminar disc (mesoderm, endoderm and ectoderm)
• Cells migrate between the two primitive layers via the primitive streak - the cells that migrate become the mesoderm
  
  • Some of the primitive mesodermal cells migrate below the hypoblast to form the neural plate

Question 14

What is the neural plate and how does it develop?

Answer 14

• The neural plate is a thickening made up of ectoderm, and lies opposing the primitive streak (formed from migrating primitive mesodermal cells)
• Neural plate develops after the inducing effect of the primitive streak and is the basis of the nervous system
• Formation of nervous tissue involved complex interactions between mesoderm and ectoderm, mediated by:
  
  • Shh and noggin
  • BMPs, wnt, FGFs

Question 15

What germ layer forms the nervous tissue?

Answer 15

Ectoderm

Question 16

How is the eye formed?

Answer 16

• As an outgrowth of the CNS (specifically the diencephalon)
  
  • This includes the retina, optic nerve and tract
• This means that the eyes are part of the CNS
• A cup is formed with inner and outer layers
  
  • Inner layer gives rise to the neuroretina
  • Outer layer gives rise to the pigment epithelium
  • [EXTRA] Retinal detachment occurs directly at this embryonic boundary
• The subarachnoid space extends to the optic disc
  
  • [CLINICAL] This means that intercranial pressure can cause the optic disc to protrude into the eye, so can be measured by looking at the papilla using an ophthalmoscope

Question 17

How does the ventricular system develop?

Answer 17

• These are formed from dilation of the space within the neural tube
• Start simple, but become more and more complex until their characteristic shape is obtained
  
  • Eventually forms two lateral ventricles, the third ventricle, the cerebral aqueduct and the fourth ventricle

Question 18

What are the different structures within the embryonic forebrain, midbrain and hindbrain?

Answer 18

• Forebrain
  
  • Telencephalon (cerebral hemispheres)
  • Diencephalon (anterior forebrain structures, including thalamus, hypothalamus, posterior pituitary, pineal gland)
  • Neural retina
  • Lens
  • (Lateral ventricle and 3rd ventricle)
• Midbrain
  
  • Mesencephalon (all midbrain structures, e.g. colliculi, tegmentum, cerebral peduncles)
  • (Cerebral aqueduct)
• Hindbrain
  
  • Metencephalon (pons and cerebellum)
  • Meyelencephalon (medulla)
  • (4th ventricle)

Question 19

What is the signalling centre for ventro-dorsal patterning? What is established by this patterning?

Answer 19

• Notochord - this is a signalling centre outside of the CNS, and is of mesodermal origin, using Shh as a signalling molecule
• Notochord induces the floor plate, which induces further differentiation along the neural tube
• Patterning also allows the establishment of motor neuron pools (somatic motor and visceral)

Question 20

What structure does the notochord induce in the neural tube?

Answer 20

Floor plate (FP), which lies ventrally, using Shh

Question 21

What does the floor plate do?

Answer 21

• Induces further differentiation throughout the neural tube
  
  • This is not limited to the spinal cord but also extends to the brainstem and base of the telencephalic vesicle

Question 22

What is the roof plate (RP)?

Answer 22

• Thickening on the dorsal side of the neural tube
• Expresses BMP4 to effect development of neurons
  
  • Specifically induces the formation of commissural interneurons (decussating interneurons)
• Dorsal side contains sensory (somatic and visceral) nerve fibres

Question 23

Is embryonic patterning of the spinal cord retained in the adult?

Answer 23

Yes, roughly

Question 24

What does rostro-caudal patterning depend on?

Answer 24

Depends on the dimensions and signals from the rhombomeres, and the location of the nulcei
WNT

Question 25

What cells facilitate neurogenesis?

Answer 25

* **Neuroepithelium** generates neurons at a very high rate * Progenitor cells (therefore partially restricted) are found within the **neuroectoderm**

Question 26

Where do most of the divisions in neurogenesis occur?

Answer 26

Next to the ventricular zones/CSF-filled ventricles

Question 27

What happens after neurogenesis?

Answer 27

* Cells then migrate out towards the pial surface/towards the skull * The first post-mitotic cells are found at this surface, which is known as the primordial plexiform zone or 'pre-plate' * This patterning method is the same within all mammals, with projenitors in the ventricular zone/subventricular zone and mature post-mitotic cells lying close to the pial membrane/pre-plate region * This migration route starts short but eventually grows longer

Question 28

What is the patterning of neurogenesis?

Answer 28

* This method of patterning is the same within all mammals, with progenitors in the VZ (ventricular zone) and SVZ (subVZ), with mature post-mitotic cells being observed close to the pial membrane/in the pre-plate region – the route starts short and then increases in length * This is initially split into two regions (marginal zone and the sub-plate), then the cortical plate develops from an inner- to outermost fashion between the two, largely transient cell layers.

Question 29

What is Spina Bifida?

Answer 29

Spina Bifida → failure of neural tube to close at caudal end Spectrum SB occulta → incomplete posterior closure of the vertebrae SB meningocele → protrusion of the meninges SB myelomeningocele → protrusion of the spinal cord itself. Often associated w/ severe disability Even w/ occulta can have lower limb weakness + sensory deficits

Question 30

What is taken during pregnancy to prevent spina bifida?

Answer 30

MTC vitamin study research group (1991) → showed folic acid supplementation ↓ incidence of neural tube defects in high-risk pregnancies by 72% Folic acid supplementation now recommended to all women trying to conceive or before W12 of gestation.

Question 31

Why is cell migration important in CNS development?

Answer 31

Neurons generated in ventricular zone must migrate to their final destination

Question 32

What are the two main types of migration?

Answer 32

*Radial migration *Tangential migration

Question 33

Describe how radial migration takes place.

Answer 33

1st wave migrates independently of glia (via somal translocation) *Extend leading processes that attach to pial surface. Nucleus then moves through cytoplasm via nucleokinesis. Trailing processes retracted from ventricular surface. *Involved simplex molecular machinery (actin/ microtubules/ filamin) Subsequent waves (90% of migrating neurons in humans) use bipolar RGCs as scaffold. *Migrating neurons attach processes to BRGCs to guide them into developing cortical plate.

Question 34

Which neurons use radial migratioon?

Answer 34

Glutamatergic neurons

Question 35

Describe tangential migration.

Answer 35

*Move parallel to surface of brain *Interneurons disperse from ganglionic eminences (GEs) in ventral forebrain to rest of brain. *Precursor cells from different GEs supply different regions of dev brain: *Medial GEs → dorsally into neocortex *Lateral GEs → anteriorly into olfactory bulb *Involved axonal guidance/ leading process extension/ nucleokinesis/ stop signal

Question 36

Which neurons use tangential migration?

Answer 36

GABAergic

Question 37

How are neural connections established?

Answer 37

* If there are lots of projections extending from one region of the brain to another, they have to interconnect in a topographic way/organised manner * Some rely upon molecular cues to reach their final destination, whereas a small proportion are able to find their way using neuronal activity * The axons and cells extend long neurites that are able to navigate within the environment through the use of growth cones * Connections are usually established when the distance between cells is minimal * The growth cone exists on the tip of the advancing neuron, using filopodia to explore the immediate environment (look like flickering fingers) * There is actin polymerisation occurring within these filopodia (can be visualised using GFP) * There is local attraction and repulsion, the insertion of new cytoskeleton and autonomous action * Growth cones respond to various positive and negative cues (e.g. contact, distance, diffusible chemicals)

Question 38

How are axons thought to be guided to their correct connections?

Answer 38

* Using molecular cues - growth cones are either attracted or repelled by these * These cues can be local (substrate-bound) or long-range (diffusible) * A given molecule can be both attractive and repulsive, depending on the interaction

Question 39

What are the final stages of neuronal patterning driven by?

Answer 39

*Cell death *Establishment of neuronal connections *Synaptic plasticity

Question 40

Why is neuronal cell death important?

Answer 40

Neuronal cell death imp at subplate of intermediate zone. Facilitates loss of dynamic + transient scaffold (for organised migration) *Vulnerable to dev. defects To increase the efficiency of existing connections as axons and dendrites link up

Question 41

What controls differentiation of neuronal precursors into their subtypes?

Answer 41

Different growth factors e.g. SOX5 in the subplate layer